Biodistribution and radiation dosimetry of the hypoxia marker F-18-HX4 in monkeys and humans determined by using whole-body PET/CT

Diagnostic Imaging, Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA.
Nuclear Medicine Communications (Impact Factor: 1.37). 12/2010; 31(12):1016-24. DOI: 10.1097/MNM.0b013e3283407950
Source: PubMed

ABSTRACT F-HX4 is a novel positron emission tomography (PET) tracer for imaging hypoxia. The purpose of this study was to determine the biodistribution and estimate the radiation dose of F-HX4 using whole-body PET/computed tomography (CT) scans in monkeys and humans.
Successive whole-body PET/CT scans were done after the injection of F-HX4 in four healthy humans (422±142 MBq) and in three rhesus monkeys (189±3 MBq). Biodistribution was determined from PET images and organ doses were estimated using OLINDA/EXM software.
The bladder, liver, and kidneys showed the highest percentage of the injected radioactivity for humans and monkeys. For humans, approximately 45% of the activity is eliminated by bladder voiding in 3.6 h, and for monkeys 60% is in the bladder content after 3 h. The critical organ is the urinary bladder wall with the highest absorbed radiation dose of 415±18 (monkeys) and 299±38 μGy/MBq (humans), in the 4.8-h bladder voiding interval model. The average value of effective dose for the adult male was estimated at 42±4.2 μSv/MBq from monkey data and 27±2 μSv/MBq from human data.
Bladder, kidneys, and liver have the highest uptake of injected F-HX4 activity for both monkeys and humans. The urinary bladder wall receives the highest dose of F-HX4 and is the critical organ. Thus, patients should be encouraged to maintain adequate hydration and void frequently. The effective dose of F-HX4 is comparable with that of other F-based imaging agents.


Available from: Mohan Doss, Mar 27, 2014
1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxia is prevalent in many solid tumors. Hypoxic tumors tend to exhibit rapid growth and aberrant vasculature, which lead to oxygen (O2) depletion and impaired drug delivery. The reductive environment in hypoxic tumors alters cellular metabolism, which can trigger transcriptional responses; induce genetic alterations; promote invasion, metastasis, resistance to radiotherapy and chemotherapy, tumor progression, and recurrence; and leads to poor local control and reduced survival rates. Therefore, exploiting the reductive microenvironment in hypoxic tumors by delivering electron-affinic, O2-mimetic radioactive drugs that bioreductively activate selectively in the hypoxic microenvironment offers a logical approach to molecular imaging of focal hypoxia. Because these agents also radiosensitize hypoxic cells, they provide an innovative approach to the therapy management of such tumors. To date, nuclear imaging of hypoxic tumor has proven to be clinically effective, whereas chemical radiosensitization by these compounds has not been helpful. The current review provides an insight into the chemistry, radiochemistry, and purification strategies for selected nitroaromatics that directly exploit the bioreductive environment in hypoxic cells. Both experimental and calculated single-electron reduction potentials of electron-affinic compounds, nitroimidazoles in particular, correlate with in vitro radiosensitizing properties, making them preferred choices for use as radiopharmaceuticals for diagnostic imaging and as sensitizers to enhance the killing effects of low-energy-transfer x-rays (O2-mimetic radiosensitization). Extensive research and careful drug design have led to the development of several potentially useful hypoxia-targeting drugs, for example, [(18)F]FAZA, [(18)F]FMISO, [(18)F]EF5, and [(123)I]IAZA, that accrue selectively in hypoxic cells. These molecular probes are now globally used in clinical hypoxia imaging, including cancer. Future innovative developments must, however, consider hypoxia-selective molecular processes and the physicochemical properties of the drugs that dictate their biodistribution, hypoxia-selective accumulation, pharmacokinetics, clearance, biochemical behavior, and metabolism. This will facilitate their ultimate transformation to effective molecular theranostics, leading to improved multimodal management of cancer. Copyright © 2015 Elsevier Inc. All rights reserved.
    Seminars in Nuclear Medicine 03/2015; 45(2). DOI:10.1053/j.semnuclmed.2014.10.005 · 3.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumour cells exhibit several properties that allow them to grow and divide. A number of these properties are detectable by nuclear imaging methods. We discuss crucial tumour properties that can be described by current radioprobe technologies, further discuss areas of emerging radioprobe development, and finally articulate need areas that our field should aspire to develop. The review focuses largely on positron emission tomography and draws upon the seminal ‘Hallmarks of Cancer’ review article by Hanahan and Weinberg in 2011 placing into context the present and future roles of radiotracer imaging in characterizing tumours.
    European journal of nuclear medicine and molecular imaging 02/2015; 42(4). DOI:10.1007/s00259-014-2984-3 · 5.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several individual clinical and preclinical studies have shown the possibility of evaluating tumor hypoxia by using noninvasive positron emission tomography (PET). The current study compared 3 hypoxia PET tracers frequently used in the clinic, [(18)F]FMISO, [(18)F]FAZA, and [(18)F]HX4, in a preclinical tumor model. Tracer uptake was evaluated for the optimal time point for imaging, tumor-to-blood ratios (TBR), spatial reproducibility, and sensitivity to oxygen modification. PET/computed tomography (CT) images of rhabdomyosarcoma R1-bearing WAG/Rij rats were acquired at multiple time points post injection (p.i.) with one of the hypoxia tracers. TBR values were calculated, and reproducibility was investigated by voxel-to-voxel analysis, represented as correlation coefficients (R) or Dice similarity coefficient of the high-uptake volume. Tumor oxygen modifications were induced by exposure to either carbogen/nicotinamide treatment or 7% oxygen breathing. TBR was stabilized and maximal at 2 hours p.i. for [(18)F]FAZA (4.0 ± 0.5) and at 3 hours p.i. for [(18)F]HX4 (7.2 ± 0.7), whereas [(18)F]FMISO showed a constant increasing TBR (9.0 ± 0.8 at 6 hours p.i.). High spatial reproducibility was observed by voxel-to-voxel comparisons and Dice similarity coefficient calculations on the 30% highest uptake volume for both [(18)F]FMISO (R = 0.86; Dice coefficient = 0.76) and [(18)F]HX4 (R = 0.76; Dice coefficient = 0.70), whereas [(18)F]FAZA was less reproducible (R = 0.52; Dice coefficient = 0.49). Modifying the hypoxic fraction resulted in enhanced mean standardized uptake values for both [(18)F]HX4 and [(18)F]FAZA upon 7% oxygen breathing. Only [(18)F]FMISO uptake was found to be reversible upon exposure to nicotinamide and carbogen. This study indicates that each tracer has its own strengths and, depending on the question to be answered, a different tracer can be put forward. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    International Journal of Radiation OncologyBiologyPhysics 02/2015; 91(2):351-359. DOI:10.1016/j.ijrobp.2014.09.045 · 4.18 Impact Factor